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PubMed2000

Molecular investigation of African isolates of Trichinella reveals genetic polymorphism in Trichinella nelsoni.

Molecular genetic studies were carried out on three isolates of Trichinella nelsoni (from Kenya, Tanzania and South Africa) and three isolates of Trichinella T8 (from South Africa and Namibia) from sylvatic carnivores and from a sylvatic swine. A probe (pT7.3) specific for T. nelsoni was obtained by screening a pUC18 genomic library. The pT7.3 sequence was 346 bp in length with an AT content of 70%. The sequence is present approximately 200 times per haploid genome. Southern blot analysis of Hind III digested DNAs of the three isolates of T. nelsoni revealed that the hybridisation patterns of the isolates from Kenya and Tanzania were identical and that they differed from that of the isolate from South Africa, indicating the presence of polymorphism in this species. A pUC18 genomic library of Trichinella T8 was also screened, and one clone (pT8.3) was found to be specific for homologous DNA by dot blot, but Southern blot analysis of DNA samples from eight genotypes showed different hybridisation signals for both Trichinella T8 and Trichinella britovi DNAs. No differences in the nucleotide sequences of the expansion segment V were observed for the T. nelsoni isolates. However, they differed from those of Trichinella T8. The presence of Trichinella T8 in Africa south of the Sahara and its genetic relationship with T. britovi remain unclear and warrant detailed investigations.

Animals↗
PubMed2000

Analysis of measles virus binding sites of the CD46 gene in patients with subacute sclerosing panencephalitis.

Measles virus (MV) binding sites of the CD46 gene were sequenced in patients with subacute sclerosing panencephalitis (SSPE) and in controls. There were 3 novel polymorphisms, including C/T at nucleotide position 38 (C/T38), G/A at position 176 (G/A176), and C/T at position 453 (C/T453), at allele frequencies of.97:.03, .99:.01, and.97:.03, respectively. The G/A176 polymorphism causes an Arg/Gln amino acid change within the essential binding sites of MV, whereas the C/A38 polymorphism causes a Ser/Phe change outside the MV binding sites. The C/T453 polymorphism does not produce an amino acid change. Two of the 40 SSPE patients and 2 of the 32 controls had both C/T38 and C/T453 polymorphisms in heterozygous patterns. One control subject, but no SSPE patients, had the G/A176 polymorphism in a heterozygous pattern. Thus, it is not likely that CD46 gene alteration has a role as a host susceptibility factor in the development of SSPE.

Adolescent↗
PubMed1990

Family studies in von Willebrand's disease by analysis of restriction fragment length polymorphisms and an intragenic variable number tandem repeat (VNTR) sequence.

We have previously identified a microsatellite variable number tandem repeat region of the nucleotide sequence ATCT within intron 40 of the von Willebrand factor (vWF) gene. By polymerase chain reaction (PCR) amplification of this region, eight major alleles have been demonstrated in the South Wales population, with an overall heterozygosity rate of 75%. Direct sequencing has shown that the alleles correspond to lengths of between six and 14 ATCT repeats. In the present study we describe the use of this variable repeat sequence and previously reported restriction fragment length polymorphisms (RFLP) to study inheritance patterns in families with type I, IIA and severe type III von Willebrand's disease (vWD). The results confirm that analysis of this precisely localized intragenic locus provides a highly informative marker for gene tracking studies in the major forms of vWD.

Base Sequence↗
PubMed2006

Major histocompatibility complex class II variation in the giant panda (Ailuropoda melanoleuca).

Habitat destruction and human activity have greatly impacted the natural history of the giant panda (Ailuropoda melanoleuca). Although the genetic diversity of neutral markers has been examined in this endangered species, no previous work has examined adaptive molecular polymorphisms in the giant panda. Here, the major histocompatibility complex (MHC) class II DRB locus was investigated in the giant panda, using single-strand conformation polymorphism (SSCP) and sequence analysis. Comparisons of DNA samples extracted from faecal and blood samples from the same individual revealed that the two materials yielded similar quantities and qualities of DNA, as well as identical SSCP patterns and allelic sequences, demonstrating the reliability of DNA isolation from panda faeces. Analysis of faecal samples from 60 giant pandas revealed relatively low number of alleles: seven alleles. However, the alleles were quite divergent, varying from each other by a range of 7-47 nucleotide substitutions (4-25 amino acid substitutions). Construction of a neighbour-joining tree and comparisons among DRB alleles from other species revealed that both similar and highly divergent alleles survived in the bottlenecked panda populations. Despite species-specific primers used and excellent faecal DNA isolated, a lower level of heterozygosity than expected was still observed due to inbreeding. There were three types of evidence supporting the presence of balancing selection in the giant panda: (i) an obvious excess of nonsynonymous substitutions over synonymous at the antigen-binding positions; (ii) trans-species evolution of two alleles between the giant panda and other felids; and (iii) a more even distribution of alleles than expected from neutrality.

Alleles↗
PubMed1995

The small cell lung cancer antigen cluster-4 and the leukocyte antigen CD24 are allelic isoforms of the same gene (CD24) on chromosome band 6q21.

Cluster-4 and CD24 cDNA's have recently been cloned from the small cell lung carcinoma (SCLC) cell line SW2 and from the erythroleukemia cell line K562, respectively. The only difference in the coding sequence, between cluster-4 and CD24 antigens is the substitution of a single base pair leading to a substitution of Val by Ala near the putative glycosylphosphatidylinositol (GPI) anchorage sites of the mature protein. Here we demonstrate that the nucleotide substitution which distinguishes the cluster-4 and CD24 antigen genes is due to an allelic polymorphism on chromosome band 6q21. In addition, we identified by Southern blotting and PCR of DNA from somatic human x hamster hybrid cell lines homologues of cluster-4/CD24 on the Y chromosome and chromosome 15. We suggest, however, that the gene on 6q21 is the active locus since the mRNA of cell lines always represents the allelic variants found on chromosome 6. The distribution pattern of this allelic polymorphism in SCLC cell lines and leukocytes of healthy donors did not reveal any obvious relationship with disease. However, it is noteworthy that homozygosity for cluster-4 was found in only one case whereas heterozygosity and homozygosity for CD24 both contribute up to 50% of the samples examined.

Alleles↗
PubMed1993

Nucleotide sequences, polymorphism and gene deletion of T cell receptor beta-chain constant regions of Pan troglodytes and Macaca mulatta.

Molecular studies in human, mouse, rat, and rabbit have demonstrated that the region of genomic DNA containing TCR C region genes has been strongly conserved during evolution. To investigate the degree of conservation of this region within the primate lineage we have undertaken analysis of the TCR constant region genes in two non-human primate species Pan troglodytes (chimpanzee) and Macaca mulatta (rhesus monkey). Constant regions of TCR beta-chains were cloned and sequenced from cDNA derived from peripheral blood T cells of healthy chimpanzees and rhesus monkeys. Two closely related C beta genes were characterized in each species corresponding to human C beta 1 and C beta 2. The chimpanzee/human similarity is greater than the rhesus monkey/human similarity as is expected from phylogenetic relationships. The amino acid sequences of corresponding C beta genes are identical between chimpanzee and human although synonymous substitutions are present at the nucleotide level. Two distinct monkey C beta 1 sequences were obtained. RFLP studies using genomic DNA from individuals of both species indicated the presence of only two C beta genes in each species. It is therefore likely that the rhesus monkey from which the sequence data are derived has a polymorphic C beta locus, which was also subsequently demonstrated in several other monkeys. Analysis of sequence data suggests that some nucleotide substitutions occurred after the chimpanzee/human line split from the rhesus monkey line approximately 25 million yr ago. These data also support the theory that specific mechanisms exist to reduce diversity in putative exon 1. Variable RFLP profiles indicated the presence of C beta polymorphism in chimpanzees and rhesus monkeys. There was also evidence for a homozygous deletion of a C beta gene in one monkey, represented by the absence of one band for each digest when compared to the band patterns of other monkeys. Variable intensities of the deletable band in other individuals suggest other monkeys may be heterozygous for this deletion. Thus rhesus monkeys demonstrate RFLP, coding sequence, and C beta gene deletion polymorphisms, with chimpanzees also demonstrating RFLP polymorphisms of C beta.

Amino Acid Sequence↗
PubMed1993

p53 gene mutations in human epithelial skin cancers.

In the present study we analysed 38 epithelial skin cancers, 19 basal cell carcinomas (BCCs), 13 squamous cell carcinomas (SCCs) and six Bowen diseases (BwDs), using a combination of polymerase chain reaction (PCR) and single-stranded conformation polymorphism (SSCP) techniques for the presence of p53 and RAS gene mutations. Whereas 48% (9/19) of the BCCs tested presented a mutated p53 gene, the frequency was lower (15%, 2/13) in our series of SCCs and negative in the BwDs. Nine of the 11 characterized mutations were single-nucleotide substitutions and, interestingly, seven of these involved CC dimers, where a C was changed into a T or a G (three C-->T transitions and four C-->G transversions). This mutational pattern, added to the fact that all the mutated tumors occurred at sun-exposed body sites, implicates UV light in their genesis. Furthermore, we observed two internal deletions of 6 and 24 bp whose flanking sequences contained two or three Cs on either strand. In addition to molecular detection, we searched for p53 protein accumulation, by immunocytochemical staining, in a subset of 23 epithelial skin tumors (nine bearing a mutation, 14 which scored negative in our assay). Three commercially available anti-p53 antibodies (PAb CM1, mAbs DO7 and 1801) were used, and 3/23 (all showing a mutated p53 gene) presented specific nuclear staining. In contrast to other reported data we could not detect any activating RAS gene mutation in our series of human skin cancers.

Base Sequence↗
PubMed2005

High-density single nucleotide polymorphism array defines novel stage and location-dependent allelic imbalances in human bladder tumors.

Bladder cancer is a common disease characterized by multiple recurrences and an invasive disease course in more than 10% of patients. It is of monoclonal or oligoclonal origin and genomic instability has been shown at certain loci. We used a 10,000 single nucleotide polymorphism (SNP) array with an average of 2,700 heterozygous SNPs to detect allelic imbalances (AI) in 37 microdissected bladder tumors from 17 patients. Eight tumors represented upstaging from Ta to T1, eight from T1 to T2+, and one from Ta to T2+. The AI was strongly stage-dependent as four chromosomal arms showed AI in > 50% of Ta samples, eight in T1, and twenty-two in T2+ samples. The tumors showed stage-dependent clonality as 61.3% of AIs were reconfirmed in later T1 tumors and 84.4% in muscle-invasive tumors. Novel unstable chromosomal areas were identified at chromosomes 6q, 10p, 16q, 20p, 20q, and 22q. The tumors separated into two distinct groups, highly stable tumors (all Ta tumors) and unstable tumors (2/3 muscle-invasive). All 11 unstable tumors had lost chromosome 17p areas and 90% chromosome 8 areas affecting Netrin-1/UNC5D/MAP2K4 genes as well as others. AI was present at the TP53 locus in 10 out of 11 unstable tumors, whereas 6 had homozygous TP53 mutations. Tumor distribution pattern reflected AI as seven out of eight patients with additional upper urinary tract tumors had genomic stable bladder tumors (P < 0.05). These data show the power of high-resolution SNP arrays for defining clinically relevant AIs.

Allelic Imbalance↗
PubMed2006

Transmission of mitochondrial DNA in pigs and progeny derived from nuclear transfer of Meishan pig fibroblast cells.

In embryos derived by nuclear transfer (NT), fusion, or injection of donor cells with recipient oocytes caused mitochondrial heteroplasmy. Previous studies have reported varying patterns of mitochondrial DNA (mtDNA) transmission in cloned calves. Here, we examined the transmission of mtDNA from NT pigs to their progeny. NT pigs were created by microinjection of Meishan pig fetal fibroblast nuclei into enucleated oocytes (maternal Landrace background). Transmission of donor cell (Meishan) mtDNA was analyzed using 4 NT pigs and 25 of their progeny by PCR-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, PCR-RFLP, and a specific PCR to detect Meishan mtDNA single nucleotide polymorphisms (SNP-PCR). In the blood and hair root of NT pigs, donor mtDNAs were not detected by PCR-SSCP and PCR-RFLP, but detected by SNP-PCR. These results indicated that donor mtDNAs comprised between 0.1% and 1% of total mtDNA. Only one of the progeny exhibited heteroplasmy with donor cell mtDNA populations, ranging from 0% to 44% in selected tissues. Additionally, other progeny of the same heteroplasmic founder pig were analyzed, and 89% (16/18) harbored donor cell mtDNA populations. The proportion of donor mtDNA was significantly higher in liver (12.9 +/- 8.3%) than in spleen (5.0 +/- 3.9%), ear (6.7 +/- 5.3%), and blood (5.8 +/- 3.7%) (P < 0.01). These results demonstrated that donor mtDNAs in NT pigs could be transmitted to progeny. Moreover, once heteroplasmy was transmitted to progeny of NT-derived pigs, it appears that the introduced mitochondrial populations become fixed and maternally-derived heteroplasmy was more readily maintained in subsequent generations.

Animals↗
PubMed2002

Linkage analysis of maternal EST cDNA clones covering all twenty-eight chromosomes in the silkworm, Bombyx mori.

A cDNA library of maternal messages was constructed from non-fertilized Bombyx mori eggs collected just after oviposition without mating. cDNA clones were identified by their nucleotide sequences and evaluated as probes for RFLP linkage analysis. Back crossed F1 segregants - by crossing an F1 female (RF02 x RF50) and a male (RF02) - were used, which takes advantage of the phenomenon that no crossing over occurs in Bombyx females. Fifteen ordered BF1 segregants gave either homozygous (homo) or heterozygous (hetero) RFLP patterns with each cDNA probe. cDNA probes on the same linkage group gave the same homo/hetero order. One hundred and fifty one out of 248 cDNA clones showed polymorphisms between RF02 and RF50, and were therefore suitable as probes for RFLP linkage analysis in the present BF1 cross. They were sorted into twenty-seven linkage groups and one independent group, by the homo/hetero pattern matrix, covering all twenty-eight chromosomes in B. mori.

Animals↗
PubMed2005

Genetic polymorphism of alpha-lactalbumin gene in riverine buffalo.

Alpha-lactalbumin (alpha-LA) is a major whey protein found in milk. Polymorphs of alpha-LA gene are reported to be significantly associated with milk production and constituent traits. Therefore, the present study was undertaken to detect polymorphism in alpha-LA at the genic level and to explore allelic variability at this locus. A total of 196 animals, belonging to four breeds of riverine buffalo viz. Bhadwari, Mehsana, Surti and Murrah were included under the present investigation. Two fragments i.e. 133 bp (Exon 1) and 159 bp (Exon 2) of alpha-LA gene were amplified by polymerase chain reaction and subsequently, single strand confirmation polymorphism (SSCP) study was carried out to identify different allelic pattern and genotypes of the animal included in the study. Both fragment of alpha-LA gene was found to be polymorphic in all the four breeds of riverine buffalo. Number of genotypes and allele varied breed to breed for both the fragments. In case of 133 bp fragment, four alleles A, B, C and D were found among different breeds of buffalo whereas in 159 bp fragment, five alleles namely A, B, C, D and E was found in different breeds. Nucleotide sequence data of different alleles showed the presence of both silent as well as functional mutation leading to variability in polypeptide chain.

Alleles↗
PubMed1994

The zebrafish egr1 gene encodes a highly conserved, zinc-finger transcriptional regulator.

The Egr family of transcriptional regulators comprises a group of genes that encode members of the Cys2-His2 class of zinc finger proteins. We have isolated a zebrafish egr1 homolog by screening a zebrafish genomic library with a mouse Egr1 zinc finger probe. Southern blotting indicated the existence of single zebrafish egr1 gene and, as in higher vertebrates, the presence of related members of a larger gene family. Sequence analysis of the zebrafish egr1 coding region revealed a high level of homology to the mouse, rat, and human egr1 genes with the notable exception of a polymorphic, triplet nucleotide repeat sequence in the region coding for the amino terminus of the Egr1 protein. The predicted DNA-binding, zinc finger domain protein sequence was strictly conserved. The 5' region of the zebrafish egr1 gene contained a variety of transcription factor binding sites, also present in the mouse gene, for serum response factor, CREB, and c-ets. The zebrafish egr1 transcript was approximately 3.4 kb in size and was expressed in adult zebrafish brain and muscle RNA, a pattern of expression similar to that observed in mice. The potential for zebrafish egr1 to function as a transcriptional regulator was tested by constructing an expression vector containing zebrafish egr1 coding sequences under the control of a cytomegalovirus promoter. This construct was found to activate transcription of a reporter plasmid bearing multiple Egr1 binding sites when transiently cotransfected into mouse 3T3 cells. Our results indicate that the structure, regulation, and function of the Egr1 gene have been highly conserved during vertebrate evolution and suggest an important role for this gene in growth and development.

Amino Acid Sequence↗
PubMed2005

Nutrigenetics in cancer research--folate metabolism and colorectal cancer.

The B vitamin folate is essential for one-carbon transfer reactions, including those related to the methylation of DNA or other substrates and nucleotide synthesis. Epidemiologic and experimental studies implicate low-folate intakes in elevated risk of colorectal neoplasia and suggest that biologic mechanisms underlying this relation include disturbances in DNA methylation patterns or adverse effects on DNA synthesis and repair. With the completion of the Human Genome Project, a vast amount of data on inherited genetic variability has become available. This genetic information can be used in studies of molecular epidemiology to provide information on multiple aspects of folate metabolism. First, studies linking polymorphisms in folate metabolism to an altered risk of cancer provide evidence for a causal link between this pathway and colorectal carcinogenesis. Second, studies on genetic characteristics can help clarify whether certain individuals may benefit from higher or lower intakes of folate or nutrients relevant to folate metabolism. Third, studies on genetic polymorphisms can generate hypotheses regarding possible biologic mechanisms that connect this pathway to carcinogenesis. Last, genetic variability in folate metabolism may predict survival after a cancer diagnosis, possibly via pharmacogenetic effects. To solve the puzzle of the folate-cancer relation, a transdisciplinary approach is needed that integrates knowledge from epidemiology, clinical studies, experimental nutrition, and mathematical modeling. This review illustrates knowledge that can be gained from molecular epidemiology in the context of nutrigenetics, and the questions that this approach can answer or raise.

Colorectal Neoplasms↗
PubMed2006

A functional variant in the CARD4 gene and risk of premature coronary heart disease.

Infection and innate immunity have been suggested as playing an important role in the pathogenesis of atherosclerosis. The recently discovered pattern-recognition receptor (PRR) proteins initiate signalling after host-pathogen interactions and several PRRs, especially the Toll-like receptor 4 (TLR4), have been shown to be involved in the development and progression of atherosclerosis. A new addition to the PRRs is CARD4, a gene that encodes the protein nucleotide-binding oligomerization domain 1 (NOD1) and that seems to be associated with barrier function in chronic inflammatory disorders. Recently, a functional variant in the CARD4 gene, the insertion-deletion polymorphism ND(1)+32656, has been associated with inflammatory barrier diseases (inflammatory bowel diseases and asthma). We analysed the frequencies of this known functional mutation in the CARD4 gene and of the two adjacent variants, rs2075822 and rs2907748, in a German sample of 1440 unrelated early onset coronary heart disease (CHD) patients and healthy controls. Genotype and haplotype data showed no evidence for a significant association of these CARD4 variants with CHD. Our results suggest that the analysed CARD4 mutations do not play a major role in the aetiology of CHD.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Inferring the evolutionary history of rice yellow mottle virus from genomic, phylogenetic, and phylogeographic studies.

Fourteen isolates of Rice yellow mottle virus (RYMV) were selected as representative of the genetic variability of the virus in Africa from a total set of 320 isolates serologically typed or partially sequenced. The 14 isolates were fully sequenced and analyzed together with two previously reported sequences. RYMV had a genomic organization similar to that of Cocksfoot mottle sobemovirus. The average nucleotide diversity among the 16 isolates of RYMV was 7%, and the maximum diversity between any two isolates was 10%. A strong conservative selection was apparent on both synonymous and nonsynonymous substitutions, through the amino acid replacement pattern, on the genome size, and through the limited number of indel events. Furthermore, there was a lack of positive selection on single amino acid sites and no evidence of recombination events. RYMV diversity had a pronounced and characteristic geographic structure. The branching order of the clades correlated with the geographic origin of the isolates along an east-to-west transect across Africa, and there was a marked decrease in nucleotide diversity moving westward across the continent. The insertion-deletion polymorphism was related to virus phylogeny. There was a partial phylogenetic incongruence between the coat protein gene and the rest of the genome. Overall, our results support the hypothesis that RYMV originated in East Africa and then dispersed and differentiated gradually from the east to the west of the continent.

Africa↗
PubMed2004

A novel FY allele in Brazilians.

The GATA box single nucleotide polymorphism (SNP) at position -33 (T>C) in Blacks silences the expression of FY*B in erythrocytes, and the substitution 265 C>T, together with 298 G>A, weakens the Fy(b) antigen (Fy(x)). Individuals with these phenotypes/genotypes who receive Fy(b+) blood are unlikely to be alloimmunized to Fy(b) because, in the presence of 265 T, the Fy(b) antigen is expressed, and in the case of -33 C, other tissues express Duffy protein and probably the Fy(b) antigen. We studied samples from 361 blood donors (182 of African ancestry and 179 of Caucasian ancestry) by haemagglutination and polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Forty Caucasian and 130 donors of African ancestry were serologically Fy(b-); among these, the majority of the donors of African ancestry had FY*B with the GATA SNP, while the majority of Caucasians typing Fy(b-) had FY*B with 265 T/298 A SNPs. Six of the Fy(b-) donors (three Africans and three Caucasians) had both GATA and 265/298 SNPs, and six donors of Caucasian ancestry apparently had a GATA SNP. Samples from two donors - one African and one Caucasian with an unusual MspA1I-RFLP pattern - were sequenced and found to have a novel SNP (145 G>T) co-existent with 265 C>T and 298 G>A SNPs. These findings highlight the importance of establishing the incidence and nature of molecular events that impact on Duffy expression in different populations.

Alleles↗
PubMed2006

A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility.

Detecting, characterizing, and interpreting gene-gene interactions or epistasis in studies of human disease susceptibility is both a mathematical and a computational challenge. To address this problem, we have previously developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension (i.e. constructive induction) thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe a comprehensive and flexible framework for detecting and interpreting gene-gene interactions that utilizes advances in information theory for selecting interesting single-nucleotide polymorphisms (SNPs), MDR for constructive induction, machine learning methods for classification, and finally graphical models for interpretation. We illustrate the usefulness of this strategy using artificial datasets simulated from several different two-locus and three-locus epistasis models. We show that the accuracy, sensitivity, specificity, and precision of a naïve Bayes classifier are significantly improved when SNPs are selected based on their information gain (i.e. class entropy removed) and reduced to a single attribute using MDR. We then apply this strategy to detecting, characterizing, and interpreting epistatic models in a genetic study (n = 500) of atrial fibrillation and show that both classification and model interpretation are significantly improved.

Atrial Fibrillation↗
PubMed2005

Applying a new generation of genetic maps to understand human inflammatory disease.

The sequencing of the human genome and the intense study of its variation in different human populations have improved our understanding of the genome's architecture. It is now becoming clear that segments of the genome that are unbroken by reshuffling or recombination during meiosis create a mosaic of DNA 'haplotype blocks'. Here, we discuss the advantages and limitations of this block structure. Haplotype blocks hold the promise of reducing the complexity of analysing the human genome for association with disease. But can they deliver on this promise? First generation maps of these block patterns, such as the admixture and haplotype maps, are now emerging and, it is to be hoped, will accelerate the discovery of alleles that contribute to susceptibility to human inflammatory diseases.

Chromosome Mapping↗